Novel compositions and methods

ABSTRACT

The disclosure provides new transmucosal and subcutaneous pharmaceutical compositions comprising 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one or 1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d 2 -3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one or comprising -(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d 4 -3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, in free base, co-crystal or salt form, together with methods of making and using them.

This application claims priority to U.S. Provisional Application No.62/476,538, filed Mar. 24, 2017, the contents of which are incorporatedherein by reference in its entirety.

FIELD

This disclosure relates to certain novel transmucosal and subcutaneouspharmaceutical formulations comprising substituted heterocycle fusedgamma-carbolines, the manufacture of such formulations, and methods ofuse thereof, e.g., in the treatment of diseases or abnormal conditionsinvolving or mediated by the 5-HT_(2A) receptor, serotonin transporter(SERT), and/or dopamine D₁/D₂ receptor signaling pathways. The inventionincludes methods of treatment and/or prophylaxis of diseases anddisorders including, but not limited to, anxiety, psychosis,schizophrenia, sleep disorders, sexual disorders, migraine, conditionsassociated with cephalic pain, social phobias, gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility andobesity; depression (including major depressive disorder (MDD)) and mooddisorders associated with psychosis or Parkinson's disease; psychosissuch as schizophrenia associated with depression; bipolar disorder(e.g., bipolar depression); and other psychiatric and neurologicalconditions, as well as to combinations with other agents

BACKGROUND

1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(sometimes referred to as4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone,or as ITI-007), has the following structure:

The Compound of Formula I is a potent 5-HT_(2A) receptor ligand (Ki=0.5nM) with strong affinity for dopamine (DA) D2 receptors (K_(i)=32 nM)and the serotonin transporter (SERT) (K_(i)=26 nM, measured using3H-imipramine binding displacement to human recombinant SERT), butnegligible binding to receptors associated with cognitive and metabolicside effects of antipsychotic drugs (e.g., H1 histaminergic, 5-HT_(2C),and muscarinic receptors). This compound is currently in clinicaltrials, i.e., for the treatment of schizophrenia, bipolar disorder anddementia including Alzheimer's disease. The Compound of Formula I, andanalogs thereof, salts thereof, and methods of treatment comprising suchcompounds, and methods of manufacturing such compounds, have beendisclosed, e.g., in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; RE39,680; RE39,679; U.S. Patent Publications2004/209864, 2010/113781, 2011/071080, 2011/112105, 2013/0202692,2015/0079172, 2017/0183350; and PCT Publication WO 2017/165843 and WO2017/117514. The contents of each of these U.S. patents, U.S. patentPublications, and PCT Publications are hereby incorporated by referencein their entireties.

Deuterated variants of ITI-007 are generally disclosed in US2017/0183350 and WO 2017/165843. The deuterated compounds are designedto slow or inhibit in vivo metabolism by substituted deuterium atoms forhydrogen atoms of ITI-007 at molecular positions which are the target ofmetabolic activity. The natural metabolites of ITI-007 arepharmacologically active, but with somewhat different receptorselectivity profiles. These deuterated derivatives can therefore providemodified pharmacokinetic profiles owing to altered rates or pathways ofmetabolism, as well as modified overall pharmacological profile due toshifting the balance between active parent species and active metabolitespecies.

One such deuterated compound is1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d₂-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one,the Compound of Formula II:

Another such deuterated compound is 1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d₄-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one,the Compound of Formula III:

The Compounds of Formula I, II and Formula III each undergo significantfirst-pass metabolism in the liver. The high rate of metabolism requiresthe administration of higher oral doses of drug than would otherwise beneeded, resulting in an increased burden on the liver, increased costsin manufacturing, difficulties in formulation and potentially higherpatient-to-patient variability in dose response. There is therefore aneed for new routes of administration that avoid first pass-metabolism,and which would result in correspondingly lower dosing requirements.

It has been disclosed that for a number of drugs transmucosal delivery,such as sublingual delivery, buccal delivery, and intranasal delivery,and subcutaneous delivery, are effective alternatives to traditionaldosage forms such as parenteral and oral dosing. Parenteral(intravenous) dosing is very effective in avoiding first-passmetabolism, but is limited in its usefulness because it requiresadministration by trained professionals, usually in a clinicalenvironment. In contrast, transmucosal delivery systems can be used toformulate drugs which can be taken by patients without professionalsupervision and can result in rapid drug absorption with minimalfirst-pass metabolism. Subcutaneous delivery similarly provides highlyeffective drug absorption with minimal first-pass metabolism, while alsoproviding the potential for delayed or extended release (compared to IVadministration).

The use of transmucosal drug delivery formulations is well known, withsublingual formulations of nitroglycerin dating back to 1847. Theseformulations involve the transfer of active drug agent across mucosalmembranes, including the oral mucosa, nasal mucosa, and the vaginalmucosa. These mucosal surface are much more permeable to drugs than theskin (keratinized epithelium) and have similar permeability as thegastrointestinal mucosa, but without the problem that GI absorption ofdrugs results in immediate passage to the liver for metabolism. Oralmucosal delivery systems include buccal and sublingual systems.

Existing transmucosal delivery systems include rapidly-disintegratingtablets and wafers, thin, dissolvable films, aerosol sprays, dissolvablegels, as well as aqueous solutions. Examples of dissolvable filmdelivery systems include those disclosed in U.S. Pat. No. 4,136,145 toFuchs, U.S. Pat. No. 4,849,246 to Schmidt, U.S. Pat. No. 5,629,003 toHorstmann, U.S. Pat. No. 5,948,430 to Zerbe, U.S. Pat. No. 9,108,340 toYang, U.S. Pat. No. 8,906,277 to Yang, U.S. Pat. No. 8,900,498 to Yang,U.S. Pat. No. 8,900,497 to Yang, U.S. Pat. No. 8,652,378 to Yang, U.S.Pat. No. 8,603,514 to Yang, U.S. Pat. No. 9,427,412 to Bryson, and U.S.Pat. No. 8,414,922 to Bryson. Other transmucosal systems are disclosedin U.S. Pat. No. 5,763,476 to Delbressine (sublingual and buccalsolutions and solids), U.S. Pat. No. 9,216,175 to Amancha (sublingualspray), U.S. Pat. No. 8,835,459 to Kottayil (sublingual spray), and U.S.Pat. No. 6,552,024 to Chen (various mucosal delivery systems). Somedrugs, however, such as apomorphine, are found to be tolerated andeffective in some transmucosal delivery forms, but not in others (seeU.S. Pat. No. 9,427,412, describing lack of efficacy or tolerability forsublingual tablets and intranasal sprays, but not for sublingual films).In addition, individual formulations must be fine-tuned to particularactive pharmaceutical ingredients to ensure reliability in delivery.Thus, while the field of transmucosal drug delivery has a long history,considerably effort is required in adapting any selected transmucosaldelivery technology to a particular active pharmaceutical ingredient.

Subcutaneous injection is also well-known in the art, and is popularlyused for the administration of insulin, morphine, methotrexate and manyother drugs and vaccines. Subcutaneous injection is often performed byphysicians and other medical personally using traditional syringes withsmall gauge needles, but there also exists many specialty devices forpatient self-administration of subcutaneous injection, such aspre-filled syringes, auto-injectors, and wearable injectors. Suchdevices include the HumatroPen for insulin injection (Eli Lilly,Indianapolis, Ind., U.S.) and the Otrexup auto-injector for methotrexateinjection (Antares Pharma, Ewing, N.J., U.S.).

There is a need for improved pharmaceutical delivery systems for thesafe, effective, reliable delivery of the Compounds for Formula I and/orthe Compound of Formula II. The present disclosure provides noveltransmucosal and subcutaneous formulations for the delivery of thesecompounds without the drawbacks of existing parenteral and oral deliverysystems.

BRIEF SUMMARY

The present disclosure is directed to novel transmucosal andsubcutaneous pharmaceutical formulations comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one,as well as deuterated variants thereof, in free base, co-crystal or saltforms. Transmucosal formulations include, but are not limited to, oral,nasal, and vaginal formulations in liquid, solid and/or aerosol forms,including, sublingual, buccal, intranasal and intravaginal tablets,wafers, films, sprays and gels.

Further areas of applicability of the present invention will becomeapparent from the detailed description provided hereinafter. It shouldbe understood that the detailed description and specific examples, whileindicating preferred embodiments of the invention, are intended forpurposes of illustration only and are not intended to limit the scope ofthe invention.

DETAILED DESCRIPTION

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by referenced in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls.

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight. The amounts given are based on the active weightof the material in free base equivalent form.

In a first embodiment, the present disclosure provides a transmucosalpharmaceutical formulation (Formulation 1) comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula I), in free base, co-crystal or salt form. Thepresent disclosure further provides the following Formulations:

-   -   1.1. Formulation 1, wherein the formulation comprises the        Compound of Formula I in free base form.    -   1.2. Formulation 1, wherein the formulation comprises the        Compound of Formula I in salt form, e.g., in pharmaceutically        acceptable salt form, optionally in amorphous solid or crystal        salt form; or in co-crystal form, e.g., in nicotinamide or        isonicotinamide co-crystal form.    -   1.3. Formulation 1.2, wherein the salt form is a tosylate,        oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt        form, optionally, wherein said salt form is a crystal salt form.    -   1.4. Any preceding formulation, wherein the formulation        comprises from 0.01 to 100 mg of the Compound of Formula I (free        base equivalent), e.g., 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30        mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to        30 mg, 20 to 30 mg, 20 to 50 mg, or 50 to 100 mg.    -   1.5. Any preceding formulation, wherein the formulation        comprises from 0.01 to 10 mg of the Compound of Formula I (free        base equivalent).    -   1.6. Any preceding formulation, wherein the formulation        comprises from 0.05 to 8 mg of the Compound of Formula I (free        base equivalent), e.g., from 0.1 to 5 mg, or from to 5 to 10 mg.    -   1.7. Any preceding formulation, further comprising one or more        hydrophilic water-soluble or water swellable polymers.    -   1.8. Formula 1.7, wherein the polymer is selected from the group        consisting of natural or modified cellulosic polymers, polymers        of ethylene oxide and/or propylene oxide, polymers comprising        acrylic acid monomers, natural or modified gums (e.g. xanthan        gum), natural or modified starches (e.g., pre-gelatinized        starches), or any mixture thereof.    -   1.9. Any preceding formulation, further comprising a hydrophobic        polymer or poorly water soluble polymer, for example, a silicone        polymer, or polyalkylene polymer (e.g., polyethylene).    -   1.10. Any preceding formulation, further comprising one or more        excipients selected from the group consisting of plasticizers,        surfactants, drying agents, flavors, sweeteners, binders,        disintegrants, humectants (e.g., polyols), wetting agents,        antioxidants, buffering agents (e.g., acids, bases and/or salts        thereof), and thickening agents (e.g., gelling agents).    -   1.11. Formula 1.10, wherein the one or more excipients are        selected from any of the following: alcohols (ethanol, glycerol,        propylene glycol), gums (e.g., acacia, guar, agar, xanthan,        tragacanth, karaya, gellan), polysaccharides and polysaccharide        derivatives (e.g., starches, dextrans, pectins, alginates,        carrageenans, cellulose, cellulose derivatives (e.g.,        carboxymethyl cellulose, methylcellulose, hydroxyalkyl        celluloses (e.g., hydroxyethyl cellulose, hydroxypropyl        cellulose, hydroxypropyl methyl cellulose)), gelatins including        non-gelling and gelling types (e.g., mammalian gelatins such as        bovine gelatin, porcine gelatins, avian gelatins, fish gelatins        (e.g., mixed high molecular weight and low molecular weight        gelatins), synthetic polymers (e.g., polyvinylpyrrolidones,        polyethylene oxide and/or polypropylene oxide polymers and        copolymers (e.g., poloxamers, such as poloxamer 188),        polyacrylate polymers (e.g., carbopols), polyamide polymers),        sugars and sugar alcohols (e.g., dextrose, lactose, galactose,        glucose, ribose, sucrose, trehalose, mannitol, maltitol,        lactitol, sorbitol, xylitol, erythritol, galactitol, inositol)        polypeptides/proteins, amino acids, inorganic or organic acids        (e.g., citric acid, lactic acid, malic acid, gluconic acid,        benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric        acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic        acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid,        formic acid) and their salts (e.g., sodium, potassium, calcium,        magnesium, lithium, ammonium salts of aforementioned acids),        inorganic or organic bases (e.g., alkali metal or alkaline earth        metal carbonates, bicarbonates, hydroxide, oxides), anionic        surfactants (e.g., sodium lauryl sulfate, sodium laureth        sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl        sarcosinate, sodium stearate), cationic surfactants (e.g.,        benzalkonium halides, cetylpyridinium halides, cetrimonium        halides, benzethonium halides), zwitterionic surfactants (e.g.,        cocamidoalkyl betaines, such as cocamidopropyl betaine),        nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g.,        polyethylene glycol polydodecyl ethers), sorbitan esters (e.g.,        sorbitan monolaurate, sorbitan monooleate, sorbitan        monopalmitate, sorbitan monostearate, sorbitan tristearate),        polyethoxylated sorbitan esters (e.g., polysorbate 20,        polysorbate 40, polysorbate 60, polysorbate 80), and        antioxidants (e.g., ascorbic acid, sodium metabisulfite, BHT,        BHA, TBHQ, propyl gallate, beta-carotene, tocopherols,        tocotrienols).    -   1.12. Formula 1.11, wherein any one or more of said excipients        are present in an amount of 0.01 to 20% by weight of the        formulation, e.g., 0.01 to 15%, or 0.01 to 10%, or 0.1 to 20%,        or 0.1 to 15% or 0.1 to 10%, or 0.5 to 10%, or 0.5 to 5%, or 1        to 5%, or 2.5 to 5%, or 1 to 3%, or 0.1 to 1%.    -   1.13. Any preceding formulation which is free of added        plasticizer, surfactant or humectant (e.g., polyol).    -   1.14. Any preceding formulation, wherein the formulation        comprises from 0.01 to 99% water, for example, from 0.01 to 10%        water, or from 0.01 to 5% water, or from 50 to 99% water, or        from 75 to 99% water, or from 25 to 75% water.    -   1.15. Any preceding formulation, wherein the formulation is a        rapidly dissolving tablet or wafer, e.g., a sublingual tablet or        wafer.    -   1.16. Any of formulations 1 or 1.1 to 1.14, wherein the        formulation is an oral spray, e.g., a sublingual spray or buccal        spray.    -   1.17. Any of formulations 1 or 1.1 to 1.14, wherein the        formulation is a rapidly dissolving film, e.g., a sublingual        film or buccal film.    -   1.18. Formulation 1.17, wherein the film is a single layer or        multi-layer film.    -   1.19. Formulation 1.17 or 1.18, wherein the film has uniform or        substantially uniform thickness.    -   1.20. Formulation 1.17, 1.18 or 1.19 wherein the Compound of        Formula I is uniformly or substantially uniformly distributed        throughout the film.    -   1.21. Any of formulations 1 or 1.1 to 1.14, wherein the        formulation is an intranasal spray.    -   1.22. Any of formulations 1 or 1.1 to 1.14, wherein the        formulation is an oral gel, e.g., a rapidly dissolving        sublingual or buccal gel.    -   1.23. Any of formulations 1 or 1.1 to 1.14, wherein the        formulation is an intravaginal formulation, e.g., an        intravaginal rapidly dissolving tablet, wafer or gel, or an        intravaginal spray or an intravaginal rapidly dissolving film.    -   1.24. Any preceding formulation wherein the Compound of Formula        I is incorporated into the formulation as microparticles (e.g.,        particles having an average diameter of less than 50 μm, less        than 30 μm, less than 10 μm, or less than 5 μm, or less than 1        μm).    -   1.25. Any preceding formulation wherein the Compound of Formula        I is incorporated into the formulation as nanoparticles (e.g.,        particles having an average diameter of less than 100 nm, or        less than 50 nm, or less than 10 nm).    -   1.26. Any preceding formulation, wherein the formulation is        absorbed by the mucosa (e.g., dissolves) in less than 30 seconds        after administration.    -   1.27. Any preceding formulation, wherein the dosage of the        Compound of Formula I is from 1 to 20% of the unit daily dosage        for oral administration, for example, 5 to 15% of the oral        dosage.    -   1.28. Any preceding formulation, wherein the formulation further        comprises the Compound of Formula II or the Compound of Formula        III or a combination thereof.    -   1.29. Any preceding formulation, wherein the formulation is        formulated for administration once per day, or twice per day, or        three times per day, or four times per day, or once every two        days, or once every three days.    -   1.30. Any preceding formulation, wherein the formulation        comprises the Compound of Formula I in tosylate salt form, e.g.,        in mono-tosylate salt form or di-tosylate salt form, or a        mixture thereof.    -   1.31. Formulation 1.30, wherein the formulation further        comprises toluenesulfonic acid, e.g., wherein the formulation        comprises the Compound of Formula I in tosylate salt form and        toluenesulfonic acid in a ratio of 1:3 to 3:1, or 1:2 to 2:1 or        1:1.5 to 1.5:1, or about 1:1.    -   1.32. Any preceding formulation, wherein the Compound of Formula        I is enriched in deuterium at one or more hydrogen atom        positions, for example, wherein at any one or more hydrogen atom        positions there is substantially greater than the natural level        of incorporation of deuterium at such positions of the structure        (e.g., greater than 0.1%, or greater than 0.5%, or greater than        1%, or greater than 5%).    -   1.33. Formulation 1.32, wherein the Compound of Formula I has        greater than 50% incorporation of deuterium at any one or more        hydrogen atom positions of the structure (i.e., greater than 50        atom % D), e.g., greater than 60%, or greater than 70%, or        greater than 80%, or greater than 90% or greater than 95%, or        greater than 96%, or greater than 97%, or greater than 98%, or        greater than 99%.    -   1.34. Any of formulations 1 or 1.1 to 1.31, wherein all hydrogen        atom positions of the Compound of Formula I are non-enriched in        deuterium (i.e., every hydrogen atom position contains the        natural abundance of deuterium or less than 0.1% deuterium).

In a second embodiment, the present disclosure provides a transmucosalpharmaceutical formulation (Formulation 2) comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d₂-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula II), in free base, co-crystal or salt form. Thepresent disclosure further provides the following Formulations:

-   -   2.1. Formulation 2, wherein the formulation comprises the        Compound of Formula II in free base form.    -   2.2. Formulation 2, wherein the formulation comprises the        Compound of Formula II in salt form, e.g., in pharmaceutically        acceptable salt form, optionally in amorphous solid or crystal        salt form; or in co-crystal form, e.g., in nicotinamide or        isonicotinamide co-crystal form.    -   2.3. Formulation 2.2, wherein the salt form is a tosylate,        oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt        form, optionally, wherein said salt form is a crystal salt form.    -   2.4. Any preceding formulation, wherein the formulation        comprises from 0.01 to 100 mg of the Compound of Formula II        (free base equivalent), e.g., 0.01 to 75 mg, 0.01 to 50 mg, 0.01        to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg,        10 to 30 mg, 20 to 30 mg, 20 to 50 mg, or 50 to 100 mg.    -   2.5. Any preceding formulation, wherein the formulation        comprises from 0.01 to 10 mg of the Compound of Formula II (free        base equivalent).    -   2.6. Any preceding formulation, wherein the formulation        comprises from 0.05 to 8 mg of the Compound of Formula II (free        base equivalent), e.g., from 0.1 to 5 mg, or from to 5 to 10 mg.    -   2.7. Any preceding formulation, further comprising one or more        hydrophilic water-soluble or water swellable polymers.    -   2.8. Formula 2.7, wherein the polymer is selected from the group        consisting of natural or modified cellulosic polymers, polymers        of ethylene oxide and/or propylene oxide, polymers comprising        acrylic acid monomers, natural or modified gums (e.g. xanthan        gum), natural or modified starches (e.g., pre-gelatinized        starches), or any mixture thereof.    -   2.9. Any preceding formulation, further comprising a hydrophobic        polymer or poorly water soluble polymer, for example, a silicone        polymer, or polyalkylene polymer (e.g., polyethylene).    -   2.10. Any preceding formulation, further comprising one or more        excipients selected from the group consisting of plasticizers,        surfactants, drying agents, flavors, sweeteners, binders,        disintegrants, humectants (e.g., polyols), wetting agents,        antioxidants, buffering agents (e.g., acids, bases and/or salts        thereof), and thickening agents (e.g., gelling agents).    -   2.11. Formula 2.10, wherein the one or more excipients are        selected from any of the following: alcohols (ethanol, glycerol,        propylene glycol), gums (e.g., acacia, guar, agar, xanthan,        tragacanth, karaya, gellan), polysaccharides and polysaccharide        derivatives (e.g., starches, dextrans, pectins, alginates,        carrageenans, cellulose, cellulose derivatives (e.g.,        carboxymethyl cellulose, methylcellulose, hydroxyalkyl        celluloses (e.g., hydroxyethyl cellulose, hydroxypropyl        cellulose, hydroxypropylmethyl cellulose)), gelatins including        non-gelling and gelling types (e.g., mammalian gelatins such as        bovine gelatin, porcine gelatins, avian gelatins, fish gelatins        (e.g., mixed high molecular weight and low molecular weight        gelatins), synthetic polymers (e.g., polyvinylpyrrolidones,        polyethylene oxide and/or polypropylene oxide polymers and        copolymers (e.g., poloxamers, such as poloxamer 188),        polyacrylate polymers (e.g., carbopols), polyamide polymers),        sugars and sugar alcohols (e.g., dextrose, lactose, galactose,        glucose, ribose, sucrose, trehalose, mannitol, maltitol,        lactitol, sorbitol, xylitol, erythritol, galactitol, inositol)        polypeptides/proteins, amino acids, inorganic or organic acids        (e.g., citric acid, lactic acid, malic acid, gluconic acid,        benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric        acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic        acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid,        formic acid) and their salts (e.g., sodium, potassium, calcium,        magnesium, lithium, ammonium salts of aforementioned acids),        inorganic or organic bases (e.g., alkali metal or alkaline earth        metal carbonates, bicarbonates, hydroxide, oxides), anionic        surfactants (e.g., sodium lauryl sulfate, sodium laureth        sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl        sarcosinate, sodium stearate), cationic surfactants (e.g.,        benzalkonium halides, cetylpyridinium halides, cetrimonium        halides, benzethonium halides), zwitterionic surfactants (e.g.,        cocamidoalkyl betaines, such as cocamidopropyl betaine),        nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g.,        polyethylene glycol polydodecyl ethers), sorbitan esters (e.g.,        sorbitan monolaurate, sorbitan monooleate, sorbitan        monopalmitate, sorbitan monostearate, sorbitan tristearate),        polyethoxylated sorbitan esters (e.g., polysorbate 20,        polysorbate 40, polysorbate 60, polysorbate 80), and        antioxidants (e.g., ascorbic acid, sodium metabisulfite, BHT,        BHA, TBHQ, propyl gallate, beta-carotene, tocopherols,        tocotrienols).    -   2.12. Formula 2.11, wherein any one or more of said excipients        are present in an amount of 0.01 to 20% by weight of the        formulation, e.g., 0.01 to 15%, or 0.01 to 10%, or 0.1 to 20%,        or 0.1 to 15% or 0.1 to 10%, or 0.5 to 10%, or 0.5 to 5%, or 1        to 5%, or 2.5 to 5%, or 1 to 3%, or 0.1 to 1%.    -   2.13. Any preceding formulation which is free of added        plasticizer, surfactant or humectant (e.g., polyol).    -   2.14. Any preceding formulation, wherein the formulation        comprises from 0.01 to 99% water, for example, from 0.01 to 10%        water, or from 0.01 to 5% water, or from 50 to 99% water, or        from 75 to 99% water, or from 25 to 75% water.    -   2.15. Any preceding formulation, wherein the formulation is a        rapidly dissolving tablet or wafer, e.g., a sublingual tablet or        wafer.    -   2.16. Any of formulations 2 or 2.1 to 2.14, wherein the        formulation is an oral spray, e.g., a sublingual spray or buccal        spray.    -   2.17. Any of formulations 2 or 2.1 to 2.14, wherein the        formulation is a rapidly dissolving film, e.g., a sublingual        film or buccal film.    -   2.18. Formulation 2.17, wherein the film is a single layer or        multi-layer film.    -   2.19. Formulation 2.17 or 2.18, wherein the film has uniform or        substantially uniform thickness.    -   2.20. Formulation 2.17, 2.18 or 2.19 wherein the Compound of        Formula II is uniformly or substantially uniformly distributed        throughout the film.    -   2.21. Any of formulations 2 or 2.1 to 2.14, wherein the        formulation is an intranasal spray.    -   2.22. Any of formulations 2 or 2.1 to 2.14, wherein the        formulation is an oral gel, e.g., a rapidly dissolving        sublingual or buccal gel.    -   2.23. Any of formulations 2 or 2.1 to 2.14, wherein the        formulation is an intravaginal formulation, e.g., an        intravaginal rapidly dissolving tablet, wafer or gel, or an        intravaginal spray or an intravaginal rapidly dissolving film.    -   2.24. Any preceding formulation wherein the Compound of Formula        II is incorporated into the formulation as microparticles (e.g.,        particles having an average diameter of less than 50 μm, less        than 30 μm, less than 10 μm, or less than 5 μm, or less than 1        μm).    -   2.25. Any preceding formulation wherein the Compound of Formula        II is incorporated into the formulation as nanoparticles (e.g.,        particles having an average diameter of less than 100 nm, or        less than 50 nm, or less than 10 nm).    -   2.26. Any preceding formulation, wherein the formulation is        absorbed by the mucosa (e.g., dissolves) in less than 30 seconds        after administration.    -   2.27. Any preceding formulation, wherein the dosage of the        Compound of Formula II is from 1 to 20% of the unit daily dosage        for oral administration, for example, 5 to 15% of the oral        dosage.    -   2.28. Any preceding formulation, wherein the formulation further        comprises the Compound of Formula I or the Compound of Formula        III or a combination thereof.    -   2.29. Any preceding formulation, wherein the formulation is        formulated for administration once per day, or twice per day, or        three times per day, or four times per day, or once every two        days, or once every three days.    -   2.30. Any preceding formulation, wherein the formulation        comprises the Compound of Formula II in tosylate salt form,        e.g., in mono-tosylate salt form or di-tosylate salt form, or a        mixture thereof.    -   2.31. Formulation 2.30, wherein the formulation further        comprises toluenesulfonic acid, e.g., wherein the formulation        comprises the Compound of Formula II in tosylate salt form and        toluenesulfonic acid in a ratio of 1:3 to 3:1, or 1:2 to 2:1 or        1:1.5 to 1.5:1, or about 1:1.

In a third embodiment, the present disclosure provides a subcutaneouspharmaceutical formulation (Formulation 3) comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula I), in free base, co-crystal or salt form. Thepresent disclosure further provides the following Formulations:

-   -   3.1. Formulation 3, wherein the formulation comprises the        Compound of Formula I in free base form.    -   3.2. Formulation 3, wherein the formulation comprises the        Compound of Formula I in salt form, e.g., in pharmaceutically        acceptable salt form, optionally in amorphous solid or crystal        salt form; or in co-crystal form, e.g., in nicotinamide or        isonicotinamide co-crystal form.    -   3.3. Formulation 3.2, wherein the salt form is a tosylate,        oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt        form, optionally, wherein said salt form is a crystal salt form.    -   3.4. Any preceding formulation, wherein the formulation        comprises from 0.01 to 100 mg of the Compound of Formula I (free        base equivalent), e.g., 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 30        mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg, 10 to        30 mg, 20 to 30 mg, 20 to 50 mg, or 50 to 100 mg.    -   3.5. Any preceding formulation, wherein the formulation        comprises from 0.01 to 10 mg of the Compound of Formula I (free        base equivalent).    -   3.6. Any preceding formulation, wherein the formulation        comprises from 0.05 to 8 mg of the Compound of Formula I (free        base equivalent), e.g., from 0.1 to 5 mg, or from to 5 to 10 mg.    -   3.7. Any preceding formulation, further comprising one or more        of water, water soluble-polymers (e.g., modified celluloses,        polyvinylpyrrolidones, polyethylene glycols), water-miscible        alcohols (e.g., ethanol, glycerin and propylene glycol), bulking        agents (e.g., sugars, sugar alcohols, and amino acids),        inorganic salts (e.g. sodium chloride, calcium chloride,        potassium chloride), buffers (e.g., carbonate and bicarbonate        salts, citrate salts, phosphate salts, Tris salts),        preservatives, antioxidants, chelating agents, and mixtures        thereof.    -   3.8. Any preceding formulation, wherein the formulation        comprises from 0.01 to 99% water, for example, from 0.01 to 10%        water, or from 0.01 to 5% water, or from 50 to 99% water, or        from 75 to 99% water, or from 25 to 75% water.    -   3.9. Any preceding formulation, wherein a substantial amount        (e.g., greater than 75% or greater than 85%, or greater than        90%) of the Compound of Formula I is absorbed immediately (e.g.,        in less than 1 minute, or less than 5 minutes).    -   3.10. Any preceding formulation, wherein a significant amount        (e.g., greater than 25%, or greater than 50% or greater than        75%) of the Compound of Formula I is not absorbed immediately        (e.g., in greater than 5 minutes, or greater than 10 minutes, or        greater than 30 minutes, or greater than 1 hour, or greater than        5 hours).    -   3.11. Any preceding formulation, wherein the formulation is        packaged for use in a pre-filled syringe, a pre-filled        auto-injector, or a sealed vial or similar container.    -   3.12. Any preceding formulation, wherein the formulation is        packaged for use as a dry solid, e.g., a lyophilized solid, for        reconstitution in a pharmaceutically acceptable solvent (e.g.,        sterile water for injection) at the point of use.    -   3.13. Any preceding formulation, wherein the dosage of the        Compound of Formula I is from 1 to 20% of the unit daily dosage        for oral administration, for example, 5 to 15% of the oral        dosage.    -   3.14. Any preceding formulation, wherein the formulation further        comprises the Compound of Formula II or the Compound of Formula        III or a combination thereof.    -   3.15. Any preceding formulation, wherein the formulation is        formulated for administration once per day, or once every two        days, or once every three days, or once per week, or once every        two weeks, or once every three weeks, or once per month, or once        every two months, or once every three months, or once every six        months.    -   3.16. Any preceding formulation, wherein the formulation        comprises the Compound of Formula I in tosylate salt form, e.g.,        in mono-tosylate salt form or di-tosylate salt form, or a        mixture thereof.    -   3.17. Formulation 3.16, wherein the formulation further        comprises toluenesulfonic acid, e.g., wherein the formulation        comprises the Compound of Formula I in tosylate salt form and        toluenesulfonic acid in a ratio of 1:3 to 3:1, or 1:2 to 2:1 or        1:1.5 to 1.5:1, or about 1:1.    -   3.18. Any preceding formulation, wherein the Compound of Formula        I is enriched in deuterium at one or more hydrogen atom        positions, for example, wherein at any one or more hydrogen atom        positions there is substantially greater than the natural level        of incorporation of deuterium at such positions of the structure        (e.g., greater than 0.1%, or greater than 0.5%, or greater than        1%, or greater than 5%).    -   3.19. Formulation 3.18, wherein the Compound of Formula I has        greater than 50% incorporation of deuterium at any one or more        hydrogen atom positions of the structure (i.e., greater than 50        atom % D), e.g., greater than 60%, or greater than 70%, or        greater than 80%, or greater than 90% or greater than 95%, or        greater than 96%, or greater than 97%, or greater than 98%, or        greater than 99%.    -   3.20. Any of formulations 3 or 3.1 to 3.17, wherein all hydrogen        atom positions of the Compound of Formula I are non-enriched in        deuterium (i.e., every hydrogen atom position contains the        natural abundance of deuterium or less than 0.1% deuterium).

In a fourth embodiment, the present disclosure provides a subcutaneouspharmaceutical formulation (Formulation 4) comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d₂-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula II), in free base, co-crystal or salt form. Thepresent disclosure further provides the following Formulations:

-   -   4.1. Formulation 4, wherein the formulation comprises the        Compound of Formula II in free base form.    -   4.2. Formulation 4, wherein the formulation comprises the        Compound of Formula II in salt form, e.g., in pharmaceutically        acceptable salt form, optionally in amorphous solid or crystal        salt form; or in co-crystal form, e.g., in nicotinamide or        isonicotinamide co-crystal form.    -   4.3. Formulation 4.2, wherein the salt form is a tosylate,        oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt        form, optionally, wherein said salt form is a crystal salt form.    -   4.4. Any preceding formulation, wherein the formulation        comprises from 0.01 to 100 mg of the Compound of Formula II        (free base equivalent), e.g., 0.01 to 75 mg, 0.01 to 50 mg, 0.01        to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg,        10 to 30 mg, 20 to 30 mg, 20 to 50 mg, or 50 to 100 mg.    -   4.5. Any preceding formulation, wherein the formulation        comprises from 0.01 to 10 mg of the Compound of Formula II (free        base equivalent).    -   4.6. Any preceding formulation, wherein the formulation        comprises from 0.05 to 8 mg of the Compound of Formula II (free        base equivalent), e.g., from 0.1 to 5 mg, or from to 5 to 10 mg.    -   4.7. Any preceding formulation, further comprising one or more        of water, water soluble-polymers (e.g., modified celluloses,        polyvinylpyrrolidones, polyethylene glycols), water-miscible        alcohols (e.g., ethanol, glycerin and propylene glycol), bulking        agents (e.g., sugars, sugar alcohols, and amino acids),        inorganic salts (e.g. sodium chloride, calcium chloride,        potassium chloride), buffers (e.g., carbonate and bicarbonate        salts, citrate salts, phosphate salts, Tris salts),        preservatives, antioxidants, chelating agents, and mixtures        thereof.    -   4.8. Any preceding formulation, wherein the formulation        comprises from 0.01 to 99% water, for example, from 0.01 to 10%        water, or from 0.01 to 5% water, or from 50 to 99% water, or        from 75 to 99% water, or from 25 to 75% water.    -   4.9. Any preceding formulation, wherein a substantial amount        (e.g., greater than 75% or greater than 85%, or greater than        90%) of the Compound of Formula II is absorbed immediately        (e.g., in less than 1 minute, or less than 5 minutes).    -   4.10. Any preceding formulation, wherein a significant amount        (e.g., greater than 25%, or greater than 50% or greater than        75%) of the Compound of Formula II is not absorbed immediately        (e.g., in greater than 5 minutes, or greater than 10 minutes, or        greater than 30 minutes, or greater than 1 hour, or greater than        5 hours).    -   4.11. Any preceding formulation, wherein the formulation is        packaged for use in a pre-filled syringe, a pre-filled        auto-injector, or a sealed vial or similar container.    -   4.12. Any preceding formulation, wherein the formulation is        packaged for use as a dry solid, e.g., a lyophilized solid, for        reconstitution in a pharmaceutically acceptable solvent (e.g.,        sterile water for injection) at the point of use.    -   4.13. Any preceding formulation, wherein the dosage of the        Compound of Formula II is from 1 to 20% of the unit daily dosage        for oral administration, for example, 5 to 15% of the oral        dosage.    -   4.14. Any preceding formulation, wherein the formulation further        comprises the Compound of Formula I or the Compound of Formula        III or a combination thereof.    -   4.15. Any preceding formulation, wherein the formulation is        formulated for administration once per day, or once every two        days, or once every three days, or once per week, or once every        two weeks, or once every three weeks, or once per month, or once        every two months, or once every three months, or once every six        months.    -   4.16. Any preceding formulation, wherein the formulation        comprises the Compound of Formula II in tosylate salt form,        e.g., in mono-tosylate salt form or di-tosylate salt form, or a        mixture thereof.    -   4.17. Formulation 4.16, wherein the formulation further        comprises toluenesulfonic acid, e.g., wherein the formulation        comprises the Compound of Formula II in tosylate salt form and        toluenesulfonic acid in a ratio of 1:3 to 3:1, or 1:2 to 2:1 or        1:1.5 to 1.5:1, or about 1:1.

In a fifth embodiment, the present disclosure provides a transmucosalpharmaceutical formulation (Formulation 5) comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d₄-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula III), in free base, co-crystal or salt form. Thepresent disclosure further provides the following Formulations:

-   -   5.1. Formulation 5, wherein the formulation comprises the        Compound of Formula III in free base form.    -   5.2. Formulation 5, wherein the formulation comprises the        Compound of Formula III in salt form, e.g., in pharmaceutically        acceptable salt form, optionally in amorphous solid or crystal        salt form; or in co-crystal form, e.g., in nicotinamide or        isonicotinamide co-crystal form.    -   5.3. Formulation 5.2, wherein the salt form is a tosylate,        oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt        form, optionally, wherein said salt form is a crystal salt form.    -   5.4. Any preceding formulation, wherein the formulation        comprises from 0.01 to 100 mg of the Compound of Formula III        (free base equivalent), e.g., 0.01 to 75 mg, 0.01 to 50 mg, 0.01        to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg,        10 to 30 mg, 20 to 30 mg, 20 to 50 mg, or 50 to 100 mg.    -   5.5. Any preceding formulation, wherein the formulation        comprises from 0.01 to 10 mg of the Compound of Formula III        (free base equivalent).    -   5.6. Any preceding formulation, wherein the formulation        comprises from 0.05 to 8 mg of the Compound of Formula III (free        base equivalent), e.g., from 0.1 to 5 mg, or from to 5 to 10 mg.    -   5.7. Any preceding formulation, further comprising one or more        hydrophilic water-soluble or water swellable polymers.    -   5.8. Formula 51.7, wherein the polymer is selected from the        group consisting of natural or modified cellulosic polymers,        polymers of ethylene oxide and/or propylene oxide, polymers        comprising acrylic acid monomers, natural or modified gums (e.g.        xanthan gum), natural or modified starches (e.g.,        pre-gelatinized starches), or any mixture thereof.    -   5.9. Any preceding formulation, further comprising a hydrophobic        polymer or poorly water-soluble polymer, for example, a silicone        polymer, or polyalkylene polymer (e.g., polyethylene).    -   5.10. Any preceding formulation, further comprising one or more        excipients selected from the group consisting of plasticizers,        surfactants, drying agents, flavors, sweeteners, binders,        disintegrants, humectants (e.g., polyols), wetting agents,        antioxidants, buffering agents (e.g., acids, bases and/or salts        thereof), and thickening agents (e.g., gelling agents).    -   5.11. Formula 5.10, wherein the one or more excipients are        selected from any of the following: alcohols (ethanol, glycerol,        propylene glycol), gums (e.g., acacia, guar, agar, xanthan,        tragacanth, karaya, gellan), polysaccharides and polysaccharide        derivatives (e.g., starches, dextrans, pectins, alginates,        carrageenans, cellulose, cellulose derivatives (e.g.,        carboxymethyl cellulose, methylcellulose, hydroxyalkyl        celluloses (e.g., hydroxyethyl cellulose, hydroxypropyl        cellulose, hydroxypropylmethyl cellulose)), gelatins including        non-gelling and gelling types (e.g., mammalian gelatins such as        bovine gelatin, porcine gelatins, avian gelatins, fish gelatins        (e.g., mixed high molecular weight and low molecular weight        gelatins), synthetic polymers (e.g., polyvinylpyrrolidones,        polyethylene oxide and/or polypropylene oxide polymers and        copolymers (e.g., poloxamers, such as poloxamer 188),        polyacrylate polymers (e.g., carbopols), polyamide polymers),        sugars and sugar alcohols (e.g., dextrose, lactose, galactose,        glucose, ribose, sucrose, trehalose, mannitol, maltitol,        lactitol, sorbitol, xylitol, erythritol, galactitol, inositol)        polypeptides/proteins, amino acids, inorganic or organic acids        (e.g., citric acid, lactic acid, malic acid, gluconic acid,        benzoic acid, toluenesulfonic acid, phosphoric acid, sulfuric        acid, hydrochloric acid, tartaric acid, oxalic acid, cyclamic        acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid,        formic acid) and their salts (e.g., sodium, potassium, calcium,        magnesium, lithium, ammonium salts of aforementioned acids),        inorganic or organic bases (e.g., alkali metal or alkaline earth        metal carbonates, bicarbonates, hydroxide, oxides), anionic        surfactants (e.g., sodium lauryl sulfate, sodium laureth        sulfate, sodium dodecylbenzenesulfonate, sodium lauroyl        sarcosinate, sodium stearate), cationic surfactants (e.g.,        benzalkonium halides, cetylpyridinium halides, cetrimonium        halides, benzethonium halides), zwitterionic surfactants (e.g.,        cocamidoalkyl betaines, such as cocamidopropyl betaine),        nonionic surfactants (e.g., fatty alcohol ethoxylates (e.g.,        polyethylene glycol polydodecyl ethers), sorbitan esters (e.g.,        sorbitan monolaurate, sorbitan monooleate, sorbitan        monopalmitate, sorbitan monostearate, sorbitan tristearate),        polyethoxylated sorbitan esters (e.g., polysorbate 20,        polysorbate 40, polysorbate 60, polysorbate 80), and        antioxidants (e.g., ascorbic acid, sodium metabisulfite, BHT,        BHA, TBHQ, propyl gallate, beta-carotene, tocopherols,        tocotrienols).    -   5.12. Formula 5.11, wherein any one or more of said excipients        are present in an amount of 0.01 to 20% by weight of the        formulation, e.g., 0.01 to 15%, or 0.01 to 10%, or 0.1 to 20%,        or 0.1 to 15% or 0.1 to 10%, or 0.5 to 10%, or 0.5 to 5%, or 1        to 5%, or 2.5 to 5%, or 1 to 3%, or 0.1 to 1%.    -   5.13. Any preceding formulation which is free of added        plasticizer, surfactant or humectant (e.g., polyol).    -   5.14. Any preceding formulation, wherein the formulation        comprises from 0.01 to 99% water, for example, from 0.01 to 10%        water, or from 0.01 to 5% water, or from 50 to 99% water, or        from 75 to 99% water, or from 25 to 75% water.    -   5.15. Any preceding formulation, wherein the formulation is a        rapidly dissolving tablet or wafer, e.g., a sublingual tablet or        wafer.    -   5.16. Any of formulations 5 or 5.1 to 5.14, wherein the        formulation is an oral spray, e.g., a sublingual spray or buccal        spray.    -   5.17. Any of formulations 5 or 5.1 to 5.14, wherein the        formulation is a rapidly dissolving film, e.g., a sublingual        film or buccal film.    -   5.18. Formulation 5.17, wherein the film is a single layer or        multi-layer film.    -   5.19. Formulation 5.17 or 5.18, wherein the film has uniform or        substantially uniform thickness.    -   5.20. Formulation 5.17, 5.18 or 5.19 wherein the Compound of        Formula III is uniformly or substantially uniformly distributed        throughout the film.    -   5.21. Any of formulations 5 or 5.1 to 5.14, wherein the        formulation is an intranasal spray.    -   5.22. Any of formulations 5 or 5.1 to 5.14, wherein the        formulation is an oral gel, e.g., a rapidly dissolving        sublingual or buccal gel.    -   5.23. Any of formulations 5 or 5.1 to 5.14, wherein the        formulation is an intravaginal formulation, e.g., an        intravaginal rapidly dissolving tablet, wafer or gel, or an        intravaginal spray or an intravaginal rapidly dissolving film.    -   5.24. Any preceding formulation wherein the Compound of Formula        III is incorporated into the formulation as microparticles        (e.g., particles having an average diameter of less than 50 μm,        less than 30 μm, less than 10 μm, or less than 5 μm, or less        than 1 μm).    -   5.25. Any preceding formulation wherein the Compound of Formula        III is incorporated into the formulation as nanoparticles (e.g.,        particles having an average diameter of less than 100 nm, or        less than 50 nm, or less than 10 nm).    -   5.26. Any preceding formulation, wherein the formulation is        absorbed by the mucosa (e.g., dissolves) in less than 30 seconds        after administration.    -   5.27. Any preceding formulation, wherein the dosage of the        Compound of Formula III is from 1 to 20% of the unit daily        dosage for oral administration, for example, 5 to 15% of the        oral dosage.    -   5.28. Any preceding formulation, wherein the formulation further        comprises the Compound of Formula II or the Compound of Formula        I or a combination thereof.    -   5.29. Any preceding formulation, wherein the formulation is        formulated for administration once per day, or twice per day, or        three times per day, or four times per day, or once every two        days, or once every three days.    -   5.30. Any preceding formulation, wherein the formulation        comprises the Compound of Formula III in tosylate salt form,        e.g., in mono-tosylate salt form or di-tosylate salt form, or a        mixture thereof.    -   5.31. Formulation 5.30, wherein the formulation further        comprises toluenesulfonic acid, e.g., wherein the formulation        comprises the Compound of Formula III in tosylate salt form and        toluenesulfonic acid in a ratio of 1:3 to 3:1, or 1:2 to 2:1 or        1:1.5 to 1.5:1, or about 1:1.

In a sixth embodiment, the present disclosure provides a subcutaneouspharmaceutical formulation (Formulation 6) comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d₄-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula III), in free base, co-crystal or salt form. Thepresent disclosure further provides the following Formulations:

-   -   6.1. Formulation 6, wherein the formulation comprises the        Compound of Formula III in free base form.    -   6.2. Formulation 6, wherein the formulation comprises the        Compound of Formula III in salt form, e.g., in pharmaceutically        acceptable salt form, optionally in amorphous solid or crystal        salt form; or in co-crystal form, e.g., in nicotinamide or        isonicotinamide co-crystal form.    -   6.3. Formulation 6.2, wherein the salt form is a tosylate,        oxalate, cyclamate, 4-aminosalicylate, or hydrochloride salt        form, optionally, wherein said salt form is a crystal salt form.    -   6.4. Any preceding formulation, wherein the formulation        comprises from 0.01 to 100 mg of the Compound of Formula III        (free base equivalent), e.g., 0.01 to 75 mg, 0.01 to 50 mg, 0.01        to 30 mg, 0.01 to 20 mg, 0.1 to 20 mg, 5 to 20 mg, 10 to 20 mg,        10 to 30 mg, 20 to 30 mg, 20 to 50 mg, or 50 to 100 mg.    -   6.5. Any preceding formulation, wherein the formulation        comprises from 0.01 to 10 mg of the Compound of Formula III        (free base equivalent).    -   6.6. Any preceding formulation, wherein the formulation        comprises from 0.05 to 8 mg of the Compound of Formula III (free        base equivalent), e.g., from 0.1 to 5 mg, or from to 5 to 10 mg.    -   6.7. Any preceding formulation, further comprising one or more        of water, water soluble-polymers (e.g., modified celluloses,        polyvinylpyrrolidones, polyethylene glycols), water-miscible        alcohols (e.g., ethanol, glycerin and propylene glycol), bulking        agents (e.g., sugars, sugar alcohols, and amino acids),        inorganic salts (e.g. sodium chloride, calcium chloride,        potassium chloride), buffers (e.g., carbonate and bicarbonate        salts, citrate salts, phosphate salts, Tris salts),        preservatives, antioxidants, chelating agents, and mixtures        thereof.    -   6.8. Any preceding formulation, wherein the formulation        comprises from 0.01 to 99% water, for example, from 0.01 to 10%        water, or from 0.01 to 5% water, or from 50 to 99% water, or        from 75 to 99% water, or from 25 to 75% water.    -   6.9. Any preceding formulation, wherein a substantial amount        (e.g., greater than 75% or greater than 85%, or greater than        90%) of the Compound of Formula III is absorbed immediately        (e.g., in less than 1 minute, or less than 5 minutes).    -   6.10. Any preceding formulation, wherein a significant amount        (e.g., greater than 25%, or greater than 50% or greater than        75%) of the Compound of Formula III is not absorbed immediately        (e.g., in greater than 5 minutes, or greater than 10 minutes, or        greater than 30 minutes, or greater than 1 hour, or greater than        5 hours).    -   6.11. Any preceding formulation, wherein the formulation is        packaged for use in a pre-filled syringe, a pre-filled        auto-injector, or a sealed vial or similar container.    -   6.12. Any preceding formulation, wherein the formulation is        packaged for use as a dry solid, e.g., a lyophilized solid, for        reconstitution in a pharmaceutically acceptable solvent (e.g.,        sterile water for injection) at the point of use.    -   6.13. Any preceding formulation, wherein the dosage of the        Compound of Formula III is from 1 to 20% of the unit daily        dosage for oral administration, for example, 5 to 15% of the        oral dosage.    -   6.14. Any preceding formulation, wherein the formulation further        comprises the Compound of Formula II or the Compound of Formula        I, or a combination thereof.    -   6.15. Any preceding formulation, wherein the formulation is        formulated for administration once per day, or once every two        days, or once every three days, or once per week, or once every        two weeks, or once every three weeks, or once per month, or once        every two months, or once every three months, or once every six        months.    -   6.16. Any preceding formulation, wherein the formulation        comprises the Compound of Formula III in tosylate salt form,        e.g., in mono-tosylate salt form or di-tosylate salt form, or a        mixture thereof.    -   6.17. Formulation 4.16, wherein the formulation further        comprises toluenesulfonic acid, e.g., wherein the formulation        comprises the Compound of Formula III in tosylate salt form and        toluenesulfonic acid in a ratio of 1:3 to 3:1, or 1:2 to 2:1 or        1:1.5 to 1.5:1, or about 1:1.

As used herein, “deuteration” refers to the substitution of a hydrogen(protium, ¹H) atom in a chemical structure with a deuterium atom (²H). Ahydrogen atom position of a structure is considered substituted withdeuterium when the abundance of deuterium at that position is enriched.The natural abundance of deuterium is about 0.02%, so a compound is“enriched” with deuterium at a specific position when the frequency ofincorporation of deuterium at that position exceeds 0.02%. Therefore, inany embodiment of a deuterated compound provided herein, any one or morehydrogen atoms may be enriched with deuterium at a level of greater than0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%, suchas, greater than 50%, or greater than 60%, or greater than 70%, orgreater than 80%, or greater than 90% or greater than 95%, or greaterthan 96%, or greater than 97%, or greater than 98%, or greater than 99%.

In all aspects and embodiments of the present disclosure comprising theCompound of Formula I, said Compound of Formula I may optionally bedeuterated at one or more hydrogen atom positions.

In all aspects and embodiments of the present disclosure comprising theCompound of Formula II, said Compound of Formula II is enriched only atthe designated positions (2,2-d₂).

In all aspects and embodiments of the present disclosure comprising theCompound of Formula III, said Compound of Formula III is enriched onlyat the designated positions (1,1,2,2-d₄).

In a second aspect, the present disclosure provides a process(Process 1) for the production of the transmucosal formulation ofFormulation 1, et seq., or Formulation 2, et seq., or Formulation 5, etseq., comprising the steps of:

-   -   (a) combining the Compound of Formula I, in free or        pharmaceutically acceptable salt form, and/or the Compound of        Formula II, in free or pharmaceutically acceptable salt form,        and/or the Compound of Formula III, in free or pharmaceutically        acceptable salt form, with suitable pharmaceutically acceptable        excipients, optionally in a suitable solvent or mixture of        solvents; and    -   (b) either (1) removing the solvent to provide a dried film,        or (2) removing the solvent to provide a dried powder suitable        for compression into tablets or wafers, or (3) remove the        solvent, or some portion thereof, to provide a solution suitable        for administration via an aerosol spray device.

In a third aspect, the present disclosure provides a process (Process 2)for the production of the subcutaneous formulation of Formulation 3, etseq., or Formulation 4, et seq., or Formulation 6, et seq., comprisingthe steps of either:

-   -   (a) Combining the Compound of Formula I, in free or        pharmaceutically acceptable salt form, and/or the Compound of        Formula II, in free or pharmaceutically acceptable salt form,        and/or the Compound of Formula III, in free or pharmaceutically        acceptable salt form, with suitable pharmaceutically acceptable        excipients in a suitable solvent or mixture of solvents for        injection, and then packaging the resulting solution for use        (e.g., in a pre-filled syringe, or in a sealed vial or similar        container, or in a pre-filled auto-injector); or    -   (b) Combining the Compound of Formula I, in free or        pharmaceutically acceptable salt form, and/or the Compound of        Formula II, in free or pharmaceutically acceptable salt form,        and/or the Compound of Formula III, in free or pharmaceutically        acceptable salt form, optionally with suitable pharmaceutically        acceptable excipients, in a suitable solvent or mixture of        solvents, and then removing said solvent(s) to obtain a dry        solid (e.g., a lyophilized solid) for packaging.

The pharmaceutical formulations disclosed herein, e.g., Formulation 1,et seq., Formulation 2, et seq., Formulation 3, et seq., Formulation 4,et seq., Formulation 5, et seq., and Formulation 6, et seq., maycomprise any suitable pharmaceutically acceptable excipients, includingbut not limited to: diluents such as starches, pregelatinized starches,lactose, powdered celluloses, microcrystalline celluloses, dicalciumphosphate, tricalcium phosphate, mannitol, sorbitol, xylitol, sugar andthe like; binders such as acacia, guar gum, gum tragacanth, gelatin,polyvinylpyrrolidones such as polyvinylpyrrolidones (PVP K-30,K-90),poly (vinyl pyrrolidone-co-vinyl acetate) (PVP-VA) and the like,hydroxypropyl celluloses, hydroxypropyl methylcellulose, celluloseacetate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) andthe like; disintegrants such as starches, sodium starch glycolate,pregelatinized starches, crospovidones, croscarmellose sodium and thelike; lubricants such as stearic acid, magnesium stearate, zinc stearateand the like; glidants such as colloidal silicon dioxide and the like;solubility or wetting enhancers such as anionic or cationic or neutralsurfactants; maltodextrin, complex forming agents such as various gradesof cyclodextrins and resins; release rate controlling agents such ashydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropylmethylcelluloses, ethylcelluloses, methylcelluloses, various grades ofmethyl methacrylates, waxes and the like; and film formers,plasticizers, colorants, flavoring agents, sweeteners, viscosityenhancers, preservatives, antioxidants, buffering agents, bulkingagents, and the like.

In some embodiments, the formulations may further comprise one or moreanti-oxidants, for example, tocopherol, butylated hydroxytoluene (BHT),propyl gallate (OPG), or and ascorbic acid, or the like. The inclusionof an anti-oxidant may further improve the chemical stability of theformulations by preventing oxidative chemical degradation of the activeingredient.

In another aspect, the present disclosure provides Formulation 1, etseq., Formulation 2, et seq., Formulation 3, et seq., Formulation 4, etseq., Formulation 5, et seq., or Formulation 6, et seq., for use intreating a disease or abnormal condition involving or mediated by the5-HT_(2A) receptor, serotonin transporter (SERT), and/or dopamine D₁/D₂receptor signaling pathways, e.g., a disorder selected from obesity,anorexia, bulimia, depression (including major depressive disorder(MDD)), anxiety, psychosis, schizophrenia, obsessive-compulsivedisorder, sexual disorders, migraine, attention deficit disorder,attention deficit hyperactivity disorder, sleep disorders, conditionsassociated with cephalic pain, social phobias, dementia (includingAlzheimer's Disease and Parkinson's dementia), gastrointestinaldisorders such as dysfunction of gastrointestinal tract motility andobesity, or bipolar disorder (e.g., bipolar depression).

In another embodiment, the invention provides a method (Method 1) forthe prophylaxis or treatment of a disease or abnormal conditioninvolving or mediated by the 5-HT_(2A) receptor, serotonin transporter(SERT), and/or dopamine D₁/D₂ receptor signaling pathways, in a patientin need thereof, comprising administering to the patient by atransmucosal or subcutaneous route, a therapeutically effective amountof the Compound of Formula I and/or the Compound of Formula II and/orthe Compound of Formula III. Further embodiments of Method 1 include:

-   -   1.1 Method 1, wherein the Compound of Formula I and/or the        Compound of Formula II and/or the Compound of Formula III is        administered via a transmucosal route (e.g., intra-orally,        intra-nasally, by buccal absorption or by sublingual        absorption).    -   1.2 Method 1.1, wherein the Compound of Formula I and/or the        Compound of Formula II and/or the Compound of Formula III is        administered in the form of a composition selected from any of        Formulation 1, et seq., or Formulation 2, et seq. or Formulation        4, et seq.    -   1.3 Method 1.1 or 1.2 wherein the Compound of Formula I and/or        the Compound of Formula II and/or the Compound of Formula III is        administered sublingually, e.g., via a sublingual film,        sublingual spray, sublingual tablet or wafer (e.g.,        fast-dissolving tablet or wafer), or a sublingual solution        (e.g., aqueous solution).    -   1.4 Method 1.1 or 1.2 wherein the Compound of Formula I and/or        the Compound of Formula II and/or the Compound of Formula III is        administered buccally, e.g., via a buccal film, buccal spray,        buccal sublingual tablet or wafer (e.g., fast-dissolving tablet        or wafer).    -   1.5 Method 1.1 or 1.2 wherein the Compound of Formula I and/or        the Compound of Formula II and/or the Compound of Formula III is        administered intraorally, e.g., via an intra-oral spray (e.g.,        an aerosol spray).    -   1.6 Method 1.1 or 1.2 wherein the Compound of Formula I and/or        the Compound of Formula II and/or the Compound of Formula III is        administered intranasally, e.g., via an intranasal spray (e.g.,        an aerosol spray).    -   1.7 Method 1, wherein the Compound of Formula I and/or the        Compound of Formula II and/or the Compound of Formula III is        administered via a subcutaneous route (e.g., a subcutaneous        injection).    -   1.8 Method 1.7, wherein the Compound of Formula I and/or the        Compound of Formula II and/or the Compound of Formula III is        administered in the form of a composition selected from any of        Formulation 3, et seq., or Formulation 4, et seq. or Formulation        6, et seq.    -   1.9 Method 1.7 or 1.8 wherein the Compound of Formula I and/or        the Compound of Formula II and/or the Compound of Formula III is        administered via a pre-filled syringe, an auto-injector, a        wearable injector.    -   1.10 Method 1.7, 1.8 or 1.9 wherein the Compound of Formula I        and/or the Compound of Formula II and/or the Compound of Formula        III is administered by the patient (e.g., is self-administered).    -   1.11 Method 1 or any of 1.1, et seq., wherein the disease or        condition is selected from obesity, anorexia, bulimia,        depression (including major depressive disorder (MDD)), anxiety,        psychosis, schizophrenia, obsessive-compulsive disorder, sexual        disorders, migraine, attention deficit disorder, attention        deficit hyperactivity disorder, sleep disorders, conditions        associated with cephalic pain, social phobias, dementia        (including Alzheimer's Disease and Parkinson's dementia),        gastrointestinal disorders such as dysfunction of        gastrointestinal tract motility and obesity, or bipolar disorder        (e.g., bipolar depression).    -   1.12 Method 1 or any of 1.1, et seq., wherein the disease or        condition to be treated requires rapid intervention, e.g., acute        anxiety, acute agitation, or acute psychosis.    -   1.13 Method 1 or any of 1.1, et seq., wherein the dosage        administered via the transmucosal (e.g., sublingual, buccal,        intranasal or intraoral route) or subcutaneous route is from 1        to 20% of the dosage administered for the same condition by the        oral route, for example, 5 to 15% of the oral dosage.

A Compound of Formula I or a Compound of Formula II and/or a Compound ofFormula III, for use in Method 1 or any of Method 1.1 et seq.

A pharmaceutical composition selected from any of Formulation 1, etseq., Formulation 2, et seq., Formulation 3, et seq., Formulation 4, etseq., Formulation 5, et seq., or Formulation 6, et seq., for use inMethod 1 or any of Method 1.1 et seq.

Use of a Compound of Formula I or a Compound of Formula II or a Compoundof Formula III in the manufacture of a medicament for transmucosal orsubcutaneous administration, e.g., a medicament in accordance with anyof Formulation 1, et seq., Formulation 2, et seq., Formulation 3, etseq., Formulation 4, et seq., Formulation 5, et seq., or Formulation 6,et seq., for use in a method of treatment according to Method 1 or anyof Method 1.1 et seq.

Methods of synthesizing the Compounds of Formula I and the Compounds ofFormula II are known in art, and include the methods disclosed in WOPCT/US08/03340 (WO 2008/112280); U.S. application Ser. No. 10/786,935;U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282;U.S. RE39680, and U.S. RE39679, and WO 2015/154025, the contents of eachof which are incorporated by reference in their entirety. Salts of theCompounds of the Invention may also be prepared as similarly describedin U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282;U.S. RE39680; U.S. RE39679; and WO 2009/114181, the contents of each ofwhich are incorporated by reference in their entirety.

Isolation or purification of the diastereomers of the Compounds of theInvention may be achieved by conventional methods known in the art,e.g., column purification, preparative thin layer chromatography,preparative HPLC, crystallization, trituration, simulated moving bedsand the like.

The pharmaceutically acceptable salts of the Compounds of Formula I, IIand III can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free base forms of these compoundswith a stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Transmucosal dosage forms are known to those skilled in the art, andgeneral procedures by which these dosage forms can be prepared have beendescribed. Examples of dissolvable film delivery systems include thosedisclosed in U.S. Pat. No. 4,136,145 to Fuchs, U.S. Pat. No. 4,849,246to Schmidt, U.S. Pat. No. 5,629,003 to Horstmann, U.S. Pat. No.5,948,430 to Zerbe, U.S. Pat. No. 9,108,340 to Yang, U.S. Pat. No.8,906,277 to Yang, U.S. Pat. No. 8,900,498 to Yang, U.S. Pat. No.8,900,497 to Yang, U.S. Pat. No. 8,652,378 to Yang, U.S. Pat. No.8,603,514 to Yang, U.S. Pat. No. 9,427,412 to Bryson, and U.S. Pat. No.8,414,922 to Bryson. The preparation of other transmucosal systems aredisclosed in U.S. Pat. No. 5,763,476 to Delbressine (sublingual andbuccal solutions and solids), U.S. Pat. No. 9,216,175 to Amancha(sublingual spray), U.S. Pat. No. 8,835,459 to Kottayil (sublingualspray), and U.S. Pat. No. 6,552,024 to Chen (various mucosal deliverysystems). The contents of each of these references is incorporated byreference herein in their entireties.

EXAMPLES Example 1A: Comparison of Pharmacokinetics Between Subcutaneous(SC) and Sublingual (SL) Dosing in Dogs

In vivo absorption and distribution of the Compound of Formula I and theCompound of Formula II, both in their tosylate salt forms, is comparedbetween subcutaneous and sublingual administration in non-cross oversequential studies in dogs.

SC Administration: Six male beagle dogs between 2 and 5 years of age arerandomized in two groups of three dogs each. Dogs in group 1 areadministered the Compound of Formula I at a dose of 1 mg/kg (free baseequivalent) in a 0.5% methylcellulose/distilled water vehicle. Dogs ingroup 2 are administered the Compound of Formula II at a dose of 1 mg/kg(free base equivalent) in a 0.5% methylcellulose/distilled watervehicle. Administration is subcutaneous in the intrascapular region viaa 22 or 23 gauge needle. Whole blood samples are collected via the dog'scephalic vein pre-dose, and at post-dose time-points 5, 15 and 30minutes, 1, 2, 4, 6, 8 and 24 hours. Following a minimum 7-day washoutperiod, the dogs are transferred to the sublingual portion of the study.

SL Administration: The dogs of group 1 are administered the Compound ofFormula I at a dose of 1 mg/kg (free base equivalent) in a 0.5%methylcellulose/distilled water vehicle. Dogs in group 2 areadministered the Compound of Formula II at a dose of 1 mg/kg (free baseequivalent) in a 0.5% methylcellulose/distilled water vehicle. Theanimals are anesthetized prior to administration of the dose usingpropofol (6 mg/kg) and anesthesia is maintained for 30 minutes using3-4.5% isoflurane. Administration is sublingual and the dosage isapplied for 30 minutes, then wiped off using unwoven gauze. Whole bloodsamples are collected via the dog's cephalic vein pre-dose, and atpost-dose time-points 5, 15 and 30 minutes, 1, 2, 4, 6, 8, 24, 36 and 48hours.

All blood samples are processed to plasma and analyzed for drugconcentrations using liquid chromatography-tandem mass spectrometry(LC-MS/MS). Area under the curve (AUC) of parent and metabolites basedon plasma versus time data are calculated using Prism 5.04 software(GraphPad Software, Inc.).

The results are summarized in Table 1A below (AUC is shown for 0-24hours):

Test Compound (1 mg/kg): Formula I Formula II SL AUC (ng-hr/mL) 734 1262Cmax (ng/mL) 259 562 Tmax (hr) 1.0 1.0 SC AUC (ng-hr/mL) 813 785 Cmax(ng/mL) 110 79 Tmax (hr) 1.0 1.0

The results demonstrate that both SC and SL dosing results in highplasma concentration and high plasma AUC. SL dosing also results insignificantly higher maximal plasma concentration of drug (Cmax)compared to SC dosing for both compounds. For the Compound of FormulaII, SL dosing also results in a significantly higher overall AUC, whilethe AUC for the Compound of Formula I shows comparable AUC between SCand SL dosing. Time to maximum plasma concentration is also the samebetween SC and SL dosing for both compounds.

Example 1B: Comparison of Pharmacokinetics Between Subcutaneous andSublingual Dosing in Dogs with Metabolite Analysis

A second study is performed substantially as described for Example 1A,except that plasma samples are analyzed for the parent (administered)compounds, as well as for the major known metabolites. Afteradministration of either the Compound of Formula I or the Compound ofFormula II, the major circulating species are found to be the parent andthe N-desmethyl metabolite. The results are summarized in Table 1B below(AUC is shown for 0-24 hours):

Test Compound (1 mg/kg): Formula I Formula II SL AUC (ng-hr/mL)-Parent507 1262 Cmax (ng/mL)-Parent 179 562 Tmax (hr)-Parent 1.0 1.0 AUC(ng-hr/mL)-Des-methyl 23 104 Cmax (ng/mL)-Des-methyl 4.0 27 Tmax(hr)-Des-methyl 1.0 1.0 SC AUC (ng-hr/mL)-Parent 560 785 Cmax(ng/mL)-Parent 76 79 Tmax (hr)-Parent 1.0 1.0 AUC (ng-hr/mL)-Des-methyl20 49 Cmax (ng/mL)-Des-methyl 4.0 1.0 Tmax (hr)-Des-methyl 1.7 1.0

These results further demonstrate that both SC and SL dosing results inhigh plasma concentration and high plasma AUC for the administeredcompounds. SL dosing also results in higher maximal plasma concentrationof drug (Cmax) compared to SC dosing for both compounds. In addition,the results show that both SC and SL dosing results in very low rates ofmetabolite formation, indicating that these routes effectively bypassthe primary site of metabolic degradation of these compounds (hepaticmetabolism). The Compound of Formula I circulated in plasma at an AUCapproximately 22 times higher for parent than metabolite after SLdosing, and 27 times higher for SC dosing. In contrast, whenadministered orally, it has been found that the Compound of Formula Iand its desmethyl metabolite circulate in plasma with AUC's of about 1:1or less. Similarly, results are shown for the Compound of Formula II(parent/metabolite ratio of about 12 for SL and about 16 for SC).

Example 2: Pharmacokinetics of Oral Dosing in Dogs

In contrast to the subcutaneous and sublingual pharmacokineticspresented in Example 1, this Example demonstrates that oraladministration results in substantially lower systemic exposure to drug,due to the high extent of hepatic first-pass metabolism. This is trueeven using doses from 2.5 times to 15 times higher than the dose used inthe SC and SL study.

As part of a larger long-term toxicology study, 20 male and femalebeagle dogs are administered either control, or the Compound of FormulaI, tosylate salt form, at a dose of 2.5, 5, 10, or 15 mg/kg. Forcontrol, the dogs are administered empty capsules. For the Compound ofFormula I, the dogs are administered normal-release oral capsules. Bloodsamples are obtained at 0.25 hours, 0.5 hours, 1 hour, 4 hours, 8 hourand 24 hours. The blood samples are processed to plasma and analyzed forconcentration of the Compound of Formula I by high-performance liquidchromatography-mass spectrometry. Cmax, Tmax and area-under-the-curve(AUC, 0-24 hours) are calculated using Phoenix WinNonlin software. Theresults are shown in Table 1 below:

Dosing: 2.5 mg/kg 5 mg/kg 10 mg/kg 15 mg/kg AUC (ng-hr/mL) 40.05 52.45142.5 248 Cmax (ng/mL) 5.51 7.72 29.0 44.5 Tmax (hr) 0.469 0.875 0.8131.63

The Compound of Formula I shows dose-dependent oral absorption, and thatthe plasma concentration achieved with even the highest-oral dose is farbelow the plasma concentration and AUC achieved from sublingual andsubcutaneous administration as shown in Example 1. Sublingual andsubcutaneous dosing of the Compound of Formula I at only 1.0 mg/kgresults in 24-hour AUC that is more than 18× higher than oral dosing at2.5 mg/kg. Sublingual and subcutaneous doing even provide 24-hour AUCabout three times higher at 1.0 mg/kg than oral dosing at 15 mg/kg.

These results taken together clearly demonstrate the large loss inexposure resulting from hepatic first pass metabolism, and theunexpectedly high improvement in exposures that are achieved from usingtransmucosal dosing systems.

Example 3: Pharmacokinetics of SC and IV Dosing in Monkeys

A study is also performed in monkeys to determine the plasmaconcentrations of both the Compound of Formula I and its majormetabolites after both SL and SC dosing at 0.5 mg/kg. Six Cynomolgusmonkeys are divided into two groups for IV and SC dosing with theCompound of Formula I. The animals are dosed in a fasting state. Bloodsamples are collected pre-dose, and at 5 minutes, 15 minutes, 1, 2, 4,6, 8, 24, 36 and 48 hours post-dose. All blood samples are processed toplasma and later analyzed by liquid chromatography-tandem massspectrometry. Samples are tested for the concentration of the Compoundof Formula I, as well as for its five major known metabolites. PKparameters are calculated using PK Solutions 2.0 software (SummitResearch Services, Colorado, US).

The results show that bioavailability (based on a comparison of IV to SCpharmacokinetics) is about 74% for the Compound of Formula I or SCadministration. Most tested metabolites are found to present at levelsbelow the limit of quantitation. Only the des-methyl metabolite and theamide metabolite (oxidation of the methylene adjacent to the N-methylgroup to a carbonyl) are found to be present in significantconcentration. The concentrations of both metabolites are found to belower after SC dosing than after IV dosing. The results are shown inTable 3 below:

Parent Des-methyl Amide Analyte: Compound metabolite Metabolite IV AUC(ng-hr/mL) 297 9.2 20 Cmax (ng/mL) 94 1.5 1.9 Tmax (hr) 0.083 1.0 4.0 SCAUC (ng-hr/mL) 220 2.3 3.3 Cmax (ng/mL) 23 0.3 0.3 Tmax (hr) 2.0 2.0 6.0

The results show that SC administration in monkeys results insubstantially lower levels of formation of the major metabolitescompared to IV administration.

What is claimed:
 1. A transmucosal pharmaceutical formulation comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula I) in free base, co-crystal or salt form, orcomprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d₂-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula II) in free base, co-crystal or salt form, orcomprising-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d₄-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula III) in free base, co-crystal or salt form.
 2. Theformulation of claim 1, wherein the formulation comprises the Compoundof Formula I or the Compound of Formula II or the Compound of FormulaIII in free base form.
 3. The formulation of claim 1, wherein theformulation comprises the Compound of Formula I or the Compound ofFormula II or the Compound of Formula III in salt form.
 4. Theformulation of claim 3, wherein the salt form is tosylate.
 5. Theformulation of claim 1, wherein the formulation comprises from 0.01 to10 mg of the Compound of Formula I (free base equivalent) or theCompound of Formula II (free base equivalent) or the Compound of FormulaIII (free base equivalent).
 6. The formulation of claim 1, furthercomprising one or more hydrophilic water-soluble or water swellablepolymers.
 7. The formulation of claim 6, wherein the polymer is selectedfrom the group consisting of natural or modified cellulosic polymers,polymers of ethylene oxide and/or propylene oxide, polymers comprisingacrylic acid monomers, natural or modified gums, natural or modifiedstarches, or any mixture thereof.
 8. The formulation of claim 1, furthercomprising one or more excipients selected from the group consisting ofplasticizers, surfactants, drying agents, flavors, sweeteners, binders,disintegrants, humectants, wetting agents, antioxidants, bufferingagents, and thickening agents.
 9. The formulation of claim 1, whereinthe formulation is a rapidly dissolving tablet or wafer, or a sublingualtablet or wafer.
 10. The formulation of claim 1, wherein the formulationis an oral spray, or a sublingual spray or buccal spray.
 11. Theformulation of claim 1, wherein the formulation is a rapidly dissolvingfilm or a sublingual film or buccal film.
 12. The formulation of claim11, wherein the film has uniform or substantially uniform thickness. 13.The formulation of claim 11, wherein the Compound of Formula I or II orIII is uniformly or substantially uniformly distributed throughout thefilm.
 14. The formulation of claim 1, wherein the formulation is anintranasal spray.
 15. The formulation of claim 1, wherein theformulation is an oral gel or a rapidly dissolving sublingual or buccalgel.
 16. The formulation of claim 1, wherein the formulation is anintravaginal formulation, or an intravaginal rapidly dissolving tablet,wafer or gel, or an intravaginal spray or an intravaginal rapidlydissolving film.
 17. The formulation of claim 1, wherein the Compound ofFormula I or the Compound of Formula II or the Compound of Formula IIIis incorporated into the formulation as microparticles.
 18. Theformulation of claim 1, wherein the Compound of Formula I or theCompound of Formula II or the Compound of Formula III is incorporatedinto the formulation as nanoparticles.
 19. The formulation of claim 1,wherein the formulation is absorbed by the mucosa or dissolves in lessthan 30 seconds after administration.
 20. A subcutaneous pharmaceuticalformulation comprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula I) in free base, co-crystal or salt form, orcomprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-2,2-d₂-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula II) in free base, co-crystal or salt form, orcomprising1-(4-fluoro-phenyl)-4-((6bR,10aS)-1,1,2,2-d₄-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one(Compound of Formula III) in free base, co-crystal or salt form.